Our current studies suggest mitochondrial dysfunction causes oxygen-associated genomic DNA damage. Because oxygen serves as an essential factor for oxidative stress, a cause of genomic instability, we have been examining the effect of modulating ambient oxygen on de novo tumorigenesis (e.g., lymphoma or colon polyp formation) in different cancer models. As oxidative stress is also involved in inflammation, we have been examining its effect on atherosclerosis. The goals of these investigations are to provide basic experimental evidence for the importance of ambient oxygen on disease pathogenesis and to obtain insights useful for developing new preventive strategies against the two major causes of human diseases.